Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone

BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 3A4 is the main CYP isozyme involved in methadone metabolism. We investigated the influence of grapefruit juice, which contains inhibitors of intestinal CYP3A, on the steady-state pharmacokinetics of methadone. METHODS: For 5 days, 8 patients undergoing methadone maintenance treatment received 200 mL water or grapefruit juice 30 minutes before and again together with their daily dose of methadone. Blood sampling for R-, S-, and R,S-methadone plasma determination was performed over a 24-hour period. CYP3A activity was determined by measuring the plasma 1'-hydroxymidazolam/midazolam ratio. RESULTS: A decrease in the midazolam ratio was measured in all patients after grapefruit juice (mean +/- SD before grapefruit juice, 9.3 +/- 5.9; mean +/- SD after grapefruit juice, 3.9 +/- 1.2; P <.05). Grapefruit juice led to a mean 17% increase in the area under the curve extrapolated to 24 hours for both enantiomers of methadone (range, 3% to 29% [P <.005]; range, -4% to 37% [P <.05]; and range, 1% to 32% [P <.01]; for R-, S-, and R,S-methadone, respectively). A similar increase in peak level and decrease in apparent clearance were measured with grapefruit juice, whereas time to peak level, terminal half-life, and apparent volume during the terminal phase of R-, S-, and R,S-methadone were not affected by grapefruit juice. No symptom of overmedication was either detected by the clinical staff or reported by the patients. CONCLUSIONS: Grapefruit juice administration is associated with a modest increase in methadone bioavailability, which is not expected to endanger patients. However, it cannot be excluded that a much stronger effect may occur in some patients, and thus grapefruit juice intake is not recommended during methadone maintenance treatment, in particular in patients initiating such a treatment

Multiple Mapping Conditioning: A New Modelling Framework for Turbulent Combustion

Turbulent combustion sits at the interface of two important nonlinear, multiscale phenomena: chemistry and turbulence. Its study is extremely timely in view of the need to develop new combustion technologies in order to address challenges associated with climate change, energy source uncertainty, and air pollution. Despite the fact that modeling of turbulent combustion is a subject that has been researched for a number of years, its complexity implies that key issues are still eluding, and a theoretical description that is accurate enough to make turbulent combustion models rigorous and quantitative for industrial use is still lacking. In this book, prominent experts review most of the available approaches in modeling turbulent combustion, with particular focus on the exploding increase in computational resources that has allowed the simulation of increasingly detailed phenomena. The relevant algorithms are presented, the theoretical methods are explained, and various application examples are given. The book is intended for a relatively broad audience, including seasoned researchers and graduate students in engineering, applied mathematics and computational science, engine designers and computational fluid dynamics (CFD) practitioners, scientists at funding agencies, and anyone wishing to understand the state-of-the-art and the future directions of this scientifically challenging and practically important field